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Study of the role of p53 protein in base excision repair in mammalian cell mitochondria

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Author(s):
Felipe Augusto Godoy
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Instituto de Pesquisas Energéticas e Nucleares (IPEN/BT)
Defense date:
Examining board members:
Valter Arthur; Luciana Francisco Fleuri; Marcia Nalesso Costa Harder; Leonardo Gondim de Andrade e Silva
Advisor: Valter Arthur
Abstract

All living organisms are constantly exposed to a variety of agents that can cause chemical and/or structural changes in DNA, affecting essential processes like replication and transcription. Throughout the evolution several strategies of DNA repair have been developed to remove these modifications, preventing the cytotoxic or mutagenic effect of these lesions. Mutations in mtDNA are often observed in numerous pathologies, reflecting metabolic changes or even attenuation of the apoptotic response to antineoplastic therapies. To maintain mitochondrial genomic integrity, some repair mechanisms are recruited to the organelle, mainly the base excision repair route, BER. In the nucleus, p53 tumor suppressor protein contributes to the maintenance of DNA stability, in part by direct stimulation of the BER pathway. In response to certain cellular stimuli, p53 translocate to the mitochondria, where it can trigger an apoptotic response. However, it has been shown previously that p53 can stimulate the catalytic activity of mitochondrial DNA polymerase, gamma polymerase (pol γ), which participates in the replication and repair of mtDNA. Thus, in this work we sought to understand, molecularly, this interaction between p53 and pol γ during a modulation of BER in mitochondria human cells, investigating if: i) p53 is physically associated with pol γ; ii) the TFAM protein modulates the role of p53 in DNA repair in mitochondria; and iii) the translocation of p53 to mitochondria is mediated by redox processes in mtDNA repair. For this, biochemical and molecular methods were used in the studies of protein interaction. Taken together, the results suggest the involvement of p53 protein in repair by base excision in mitochondria of human cells, and dependence of its interaction with TFAM and pol γ to support this pathway. This reinforces the importance of these proteins for the maintenance of mitochondrial genomic stability and probably for mitochondrial function. (AU)

FAPESP's process: 11/13553-2 - Research into the role of p53 in base excision repair in mitochondria of mammalian cells
Grantee:Felipe Augusto Godoy
Support Opportunities: Scholarships in Brazil - Doctorate